Chapter 3 - Behavioral Outcome Measures for the Assessment of Sensorimotor Function in Animal Models of Movement Disorders
Introduction
The relationship between dopamine (DA) and movement has been studied in depth since the discovery of DA in the brain during the late 1950s and its association with the disorder Parkinson's disease (PD) soon thereafter. In PD, DA neurons in the substantia nigra progressively degenerate leading to motor abnormalities including resting tremor, bradykinesia, rigidity, and gait disturbances. A number of neurotoxins have been used to model the loss of nigrostriatal DA neurons seen in PD, the most extensively studied model being the 6-hydroxydopamine (6-OHDA) rat model. More recently, the discovery of genetic forms of PD has led to a new generation of novel genetic mouse models with the most detailed behavioral characterization performed in mice that overexpress the presynaptic protein alpha synuclein. In both models sensorimotor tests that are sensitive to dysfunction and loss of nigrostriatal DA neurons have been developed and are important tools in providing endpoint measures for preclinical testing of potential therapeutic treatments for PD. Although the tests described in this chapter have been used in models of PD, they are also applicable to other types of movement disorders such as stroke and spinal cord injury (Schallert et al., 2000).
Section snippets
Sensorimotor Tests for Unilateral 6-OHDA Rat
The toxin 6-OHDA is widely used to create animal models of PD (Kostrzewa and Jacobwitz, 1974, Schallert and Wilcox, 1985, Ungerstedt, 1968, Ungerstedt, 1971). 6-OHDA does not cross the blood–brain barrier and therefore is injected directly into the substantia nigra. Once in the cell, 6-OHDA forms cytotoxic products like hydrogen peroxide (Heikkila and Cohen, 1971), superoxide, and hydroxy radicals (Cohen and Heikkila, 1974, Heikkila and Cohen, 1973), leading to cell death.
Rats with unilateral
Sensorimotor Tests for Genetic Mouse Models
Within the past decade several genetic mutations causing rare familial cases of PD have been identified. Mutations in the presynaptic protein alpha synuclein were some of the first mutations to be described (Chartier-Harlin et al., 2004, Kruger et al., 1998, Polymeropoulos et al., 1997, Singleton et al., 2003). Soon after this, genetic mice carrying similar mutations were generated. In addition to mice with mutations associated with familial forms of PD, there have also been mice generated that
Acknowledgements
This work was funded by American Parkinson Disease Association and the Chen Family.
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